DE1924251A1 - Process for the preparation of allyl phosphonic acid and allyl phosphonic acid derivatives - Google Patents

Description

'IfEKQK 4 CO., IXO.
126 East Lincoln Avenue, Bahway, New Jersey 07065, V, St.,

Process for the preparation of allyl-phoephone acid and allyl phosphonic acid serlvates

The present invention relates to a new and nüteliohee process for the division of propenyl-phosphonic acid and its agents and salts, in particular a process for the preparation of propenyl-phosphonic acid and its esters and bears by means of old tele transition metals-catalyzed omerization of the double bond corresponding allyl-phosphonstture or the corresponding allyl'-phoephcnats. The propenylphosphonstture and fropenylphophonato, which are manufactured according to the invention, are valuable intermediates in the synthesis of Ct) - (CiS-I _t 2 »lpo2qfpropyl) * pho8pho © e ^ re and their compounds, which compounds both have high anti-bacterial activity against gram-positive as au @ h gram «unfold negative bacteria ·

With regard to the method the present invention therefore check let _s so that they describe on the Konieption a method sur producing propenyl phosphonsäur * and their esters and Salsen based, gensäea allyl-Phoenician

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Phonic acid or an ester or a salt of allyl -phoaphonic acid in a suitable solvent the more catalytic! Subject to the effect of a compound of a transition metal will.

The present invention is based on the finding that In Presence of a transition Metallkatalyaatore the double bond in the allyl-phobphonic acid or an AHyl-phoaphonat eioh with formation of the corresponding propenyl-phosphonic acid esp. of propenyl-> phosphonate in di © 1,2-S division .shifts. The isomerization proceeds easily under a mild condition. without undesirable, competing impulsive reactions.

Vie gasified above are used as the starting material for the

according to the method AHyl-phosphonsäui ³ ® © # <§r is & Qf @ f3 © p salts thereof are used. The type ä®a v © & *? @ AdeteEB A phosphonic acid ester does not

method used; Everyone wüaaofet ©

A suitable exit office is allyl «ph © rinsing stture esters, the all starting materials

are therefore belspielsweiee Mon © -

.phosphonates, such as methyl and

Ethyl- and diethyl-allyl-phoephcmat, M @ thjrl-Sfhyl-allyl-pboephonat, Propyl and bipropyl ailyl phosphonate, n-butyl and di-n-butyl-allyl-phosphonate »n-hexyl- and di-n-hexylallyl-phosphonate, A © yl η hexyl-allyl-phoaphonate, n-ootyl- and di-n-octyl-allyl-phosphonate and tert-butyl-n-octyl-allyl-phosphonate; Mono- and di-lower-alkenyl-allyl-phoapbonate, like vinyl and bivinyl allyl phosphonate, allyl and piallyl « allyl pboephonate, propenyl and dipropenyl allyl phosphonate,

Propenyl-crotyl-allyl-pboaphonat and crotyl- and diorotyl-

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allyl-phoaphonate; Mono- r <nd di-low-alkynyl-allyl phosphbo nate, such as ethynyl and diethinyl allyl phosphonate, propargyl * and dipropargyl allyl phosphonate and ethynyl propargyl allyl phosphonate; Mono · 'and Bicycle -niefirig-allcyl-allyl-phoBphonate, such as cyolopropyl ~ and dicycloprapylallyl phasphonate, cyclopentyl and dicyclopentyl-allyl-phoephonate, cyelopropyl · cyclohexyl "allyl-phoaphonate and cyclohexyl" and dicyclohexylallyl-phoaphonate; Mono- and diaryl-allyl-phoephonates, such as Phenyl- and diphenyl-allyl-phoephonate and naphthyl- and dinaphthyl-allyl-phasphonate; and mono and diaralkyl allyl phosphonates, such as bentsyl and dibenzyl allyl phosphonate and Tolyl- and ditolyl-allyl-phoaphonate. This illyl-phosphonic acid-eeter are either known compounds or can be prepared by conventional methods fully described in the literature

If the use of ally1-ptacsphonic acid as a starting material is desired, it is easily made by acid hydrolysis of one Allyl'-phoephonic acid eatere, as described above, obtain. Allyl-phoaphonic acid can conveniently be produced in this way be done by egg ethyl allyl phoaphonat with a aqueous mineral acid, such as hydrogen chloride or sulfuric acid, is treated. The reaction mixture can, if desires to be heated to about 80 to 120 ° C, and the hydrolysis is usually completed in about 1 to 15 hours. the Allyl · * phesphonic acid can then from the reaction mixture to! conventional methods.

Salts of ally1-phosphonic acid that can be used as starting materials are, for example, mono- and dialkali » metal and mono- and alkaline earth metal salts, such as

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wise sodium and disodium allyl phosphonate, potassium and Dipotassium allyl phosphoaate, calcium allyl ^ phasphonate, barium allyl phosphonate, Magnesium - allyl phosphonate and the like « Ammonium and organic amine salts such as Ammonium and diammonium allyl phosphonate, methylammonium "· and Dimethylammonium-allyl-phoephonat, Äthylammonium- and Diethyl aramoniura allyl phosphonate, benjylammonium and dibenzylammonium allyl pb phosphonate and the like can also be used as raw materials. These salts are Expediently prepared from allyl phosphonic acid by conventional methods for salt formation. .

The isomerization reaction according to the invention is carried out in the presence a proton donating solvent carried out, not only as a solvent but also as a co-catalyst is used for isomerization. Any proton donating solvent can be used, such as water; Alcohols such as methanol, ethanol, propanol and Butanol; Ketones such as acetone and methyl ethyl ketone; Carboxylic acids such as acetic and trifluoroacetic acid; and mineral acids, such as hydrochloric and sulfuric acid. If acidic solvents and especially if mineral acids are used, it may be desirable to also use a small amount of an inert organic solvent such as dioxane or tetrahydrofuran in order to increase the solubility of the starting material in the reaction medium. In addition, solvents that in and of themselves do not donate protons can be made protons donated by the reaction is carried out in the presence of hydrogen. In this way, inert organic solvents such as hexane, benzene, petroleum ether, dioxane, tetrahydrofuran,

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Al Merck & Co *, Zno. "12

P X9 24 251.4 g August 28, 1969

Dimethylformamide, chloroform, methylene chloride, and the like be used; the reaction is carried out in an Oruok vessel Carried out in absolute hydrogen atmosphere.

The transition metal catalysts used in the process according to the invention are compounds of transition metals such as iron * nickel, cobalt, ruthenium » Rhodium, palladium, osmium, iridium, platinum, molybdenum, manganese and chromium. Typical compounds of transition metals, which can be used as catalysts are, for example Elsen-pentaearbonyl, nickel-aoetoaoefconafc, NiIckel-ehlorld-pyridine complex, Cobalt-00t »carbonyl. Rhodiumtriehlorld, Palladium-Diohlorid, Palladlum-Diaoetat-TriKthylaluminium » Iridlum tribromide, Chloroplatlnshure, Ruthenlumdiohiorldotetra-triphenylphosphine, Osmium ootaosrbonyl " Iridiun-tribromld ^ Ruthenium-elilorld ^ tetra-triphenylphosphhln, MolybdKn-hexaoarborsyl, Kaiigan-deeaearbos ^ l and chromium-trlsaoetoaoetonat or mixtures thereof.

In general, the @ rfä ^ duns @ gesiils @ # Vepfasreit is carried out in such a way that Allyl -phospfeoiss 8ur @ your emits an Ister or a SbXz of the same solution in a proton

with & ^ m ^ k &% mlwtia <sh.% n amount 3lri.ee Hbtrsangs-contact ^ ird "Wed used Kfttaly @ atorm @ iigs - takes care of about 0.1 to © about 10.0 3" mostly "5 $ des AlSfl-pho ^ phonaaurs-Auajsangeroat «rials. The RwMtion canoe bsi a temperature its Bertloh from about to sweet? BHQtefl ^ esiteiaperatur des

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Eb is familiar to the person skilled in the art that propenyl-phoaphonic acid or their esters and salts as a result of the 1, delivery of the Dop " pel bond, in which ice or trans? ore can be present. The method according to the invention is not stereo-specific, and propenyl-pbosphonata produced by this process «» ren, esters or salace are mixtures of ice and trän® »· Isomers. These mixtures of ice and trane xeomers are grounded by methods customary in technology, SoB. by Ohromatograpbie, vapor phase chromatography » Distillation and fractional crystallization,! © icsht separately «.

As ofeen ang®gebeö _t erffeämgjgegeiaigs bergest © !! * © propenyl phci8phoj> 5? Äure or esters thereof VSAA B & # lm iwieob eProducts bii d * r synthesis voäa 1 _f 2-2porypropyl) -phöspbocsäurt uuä
bindings and iaabesonder® die («-)«
Bacillus, Bepfeti "ichia _t Staptejl © e © © Brille i _f Pathogen", "ifisclilieeslicli whose g © gös Änfii) f © flk @ StÄmae, such as Bacillus subtiiis, coil, Salmonella schotttiuelleri,
monella pulioruü, Proteus ralgeria,
morganii, Stäphjlococoue aureue and Staptiyi @ c§d @ <sue pyogen @@ «'So can (£) ~ (eis ~ 1 _t 2- £ pozyprewyl) ~ phoephone acid and his sala you used pharmaceutical organisms "ahnäTBtlichea and Sr2tIieben equipment and other villi, which are subject to infection by such organisms" In a similar way they can be used for separating certain microorganisms from Hikroorganismen-Hisöbungen ..

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The cis-propenyl-phosphonic acid prepared according to the invention and its salts are converted into racemic (+) - (cis ··!, 2 ~ epoxypro ~ pyl) -phoaphonic acid by treating all of them with an epoxidizing agent. The epoxidation is accomplished, for example, by reacting the ices ~ ro.penyl ~ -phosphoric acid or a salt thereof with hydrogen peroxide in the presence of a neutral tungstic acid salt as a catalyst. Ammonium tungstate, for example, is typical of such tungstic acid salts; Alkali metal tungstates such as sodium * or potassium tungstate; Alkaline earth tungstates, such as calcium or barium tungstate; and other metal tungstates such as zinc tungstate, tin tungstate, aluminum tungstate, and the like. The catalyst can be made up to the reaction mixture as such or as a solution, or it can be prepared in the reaction mixture ^,? n «3tungstic acid is added, which has been made sufficiently basic to form the desired tungstic acid salt. The reaction can be carried out at temperatures between about 30 and about 90 ° by dissolving the cis-propenyl-phosphonic acid or a salt thereof in water, adjusting the pH of the solution to about 5.5 with a base such as sodium carbonate to 6.0 (this step is unnecessary if a salt is used), the catalyst is added and then the hydrogen peroxide is added. After the reaction has ended, (+) ~ (cis ~ 1, 2 ~ * epoxypropyl) <= - phosphonic acid is obtained from the reaction mixture as a salt by evaporation to dryness.

The cis-propenyl-phosphonic acid esters produced by the process according to the invention are in {+) - (cio-1,2-epoxy « propyl) ~ phosphonic acid or its salts converted by they are first released into the free by conventional acid hydrolysis

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Acid or a salt thereof transferred and then after the methods described above can be epoxidized.

The one remaining after the isolation of the corresponding cis isomers trans-propenyl-phosphonic acid and its esters and salts are not used directly for making the antibiotic effective (+) - (cis-1,2-epoxypropyl) -phoephonic acid or their salts are used. These are trans connections However, if they undergo further treatment with transition metal catalysts according to the methods already described are subjected to a cie-Ztrans-Oleiohgewiohtsmlsohung converted from which the οIs isomer isolated as before can be. In this way the trans isomer serves as Source of additional eis isomer, which as before in antibiotisoh effective end products can be converted.

The bedded mode for carrying out the present invention will be illustrated in the following examples. It goes without saying that the invention is not limited by these examples target.

example 1 Dl & thyl allyl phosphonate

0.5 Get triethyl phosphite are placed in a flask equipped with a Fraktionlerkolonne flask and heated with an oil bath at 165 to 175 ⁰ C. When the temperature has reached 100 ^° C., the addition of 0.5 mol of allyl bromide is started. The addition takes place at the same rate as the ethyl bromide distills. After the addition is complete, the reaction mixture is fractionated to obtain the diethyl allyl phosphonate.

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If you have the required molar amounts of appropriately substituted Phoaphites in the process described above any desired allyl phosphonate can be used obtain.

example Allyl phosphonic acid

9 »7 g of di-n-butyl allyl phosphonate are concentrated in 80 ml Chlorinated acid under reflux for 15 hours cooked. The reaction mixture is cooled to room temperature and concentrated in vacuo with heating. 50.0 ml of water are added to the residue and the evaporation is repeated. The residue is dissolved in ether and washed with water extracted. The aqueous solution is evaporated and the residue purified by dissolving it in ether, extracting it with water and evaporating the aqueous suction.

By repeating the hydrolysis described above, allylic acid can be obtained from any desired allylic acid ester produce"

Example 3

eia-propenyl ^ phosphonic acid

10.0 g of diethyl cis-propenyl-phoaphonate are refluxed in 100 ml of concentrated hydrochloric acid for 12 hours cooked. The reaction mixture is cooled to room temperature and concentrated in vacuo with heating. 50.0 ml Water are added to the residue and evaporation

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to

will be repeated. The residue is dissolved in ether and extracted with water. The aqueous extract is evaporated and the residue purified by being dissolved in ether and extracted with Waaser and evaporated the aqueous extract will.

By repeating the hydrolysis described above, ice can be obtained Propenyl-phoephonic acid from any desired cis-phoephonic acid ester getting produced.

B e i β ρ 1 e 1 4_

Hatriura allyl phoephonate

0.2 mol of allyl ^ phosphonic acid are dissolved in 100 ml of water, The pH of the aqueous solution is adjusted to 5.5 to 6.0 by adding 0.2 Hol of sodium bicarbonate. The solution is evaporated to dryness.

Example Diethyl Cl8 "propynyl" pboBphonate

20.0 g of diethyl allyl phosphonate are added to a solution of 0.2 g of Rhodlum trichlorld and 20.0 ml of ethanol, and the mixture is heated to 60 ° C. for 1 hour. The solvent is removed under reduced pressure and the residue is taken up in hexane. The catalyst is filtered off. Piltrate is concentrated to dryness. One obtained from cis and trans diethyl propenyl phosphonate. This is distilled under reduced pressure through a practical colosme, u "the ice and the tressis-Xu © sere zm tr © ma © a _o (cis" * Sledpunkt 142 ° G at 13'um) "

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Example 6

He bhyl ethyl cig propenyl phosphonate

20.0 g of methyl ethyl allyl phosphonate, 0.2 g of chloroplatinic acid, 0.3 g of tin (II) chloride and 100 ml of trifluoroacetic acid are mixed and heated to 60 ° C for 2 hours diluted with hexane and filtered to remove the catalyst. The filtrate is evaporated to dryness. A mixture of cis and trans methyl ethyl propenyl phosphate is obtained. The mixture is chromatographed on a column of a mixture of 180.0 g of silica gel and 150.0 g of Super-cel using chloroform as the eluent. The port step is monitored by thin layer chromatography (silica gel, 10 % MeOH in CHCl, evolution of iodine). After the product begins to elute, 75 ml portions are collected. A clean separation of the isomers is achieved.

Example 7 Allyl ~ cl3 "propenyl" phosphonate

To 20.0 ml of propanol, 20.0 g of allyl allyl phosphonate and Given 0.5 g of iron pentaearbonyl. The mixture is 3 hours heated to 80 ° C for a long time. The solvent is removed under reduced pressure and the residue is taken up in hexane. The hexane solution is filtered and the piltrate concentrated to dryness. A mixture of ice and trans-allyl propenyl phosphonate. 1.0 g of the mixture becomes in an aerograph autoprep vapor phase chromatograph un ~ using a 9.525 mm ("three-eights inch ·») column

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($ 15 SE JO) treated to a separation of the cis- and trans- leameren to obtain.

Example 8
Dipropargyl cis propenyl phosphonate

The procedure of Example 4 is repeated, using 20.0 g Dipropargyl allyl phosphonate instead of diethyl allyl phosphonate, 0.3 g hickel acetoacetonate instead of rhodium trichloride and 50.0 ml of acetone can be used in place of ethanol.

Example 9
Cyclopropyl-cls ° -propenyl "phOBphonate

The procedure of Example 4 is repeated, using 20.0 g Cyclopropyl allyl phosphonate instead of diethyl allyl "phO3 ~ phonate, 50.0 ml methyl ethyl ketone instead of ethanol and 0 * 2 Cobalt octacarbonyl used instead of rhodium trichloride will.

Example 10
Diphenyl-ci8 "propenyl ° phosphonate

The procedure of Example 4 is repeated using 20.0 g Diphenyl allyl phosphonate instead of diethyl allyl phosphonate, 100.0 ml of acetic acid instead of ethanol and 0.5 g of palladium diacetate triethylaluminum instead of rhodium trichloride be used.

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Example 11
Dibenzyl-cia-propenyl-phoaphonate

The procedure of Example 4 is repeated with 20.0 g Dibenzyl- »llyl-phosphonate instead of bioethyl-allyl-phoaphonate, 20.0 ml of butanol instead of ethanol and 0.5 g of Iridlum-trlbromid used instead of rhodium trichloride will.

Example 12
Diiaopropyl cis propenyl phosphonate

The procedure of Example 4 is repeated with 20.0 g EU a opropyl-allyl-phosphate instead of dietbyl-allyl ^ phoephonat, 20.0 ml of methanol instead of ethanol, and 0.2 g of ruthenium-dlchlorid-tetra-triphenylphosphine instead of Rhodium trichloride (cia-Sledepunfct 49 ° C at 0.13 mm) can be used.

Example 13
cla-propenyl-phosphonic acid

The procedure of Example 4 is repeated, using 20.0 g Allyl phosphonic acid instead of diethyl allyl phosphonate, §0.0 valley water instead of ethanol and 0.3 g osmium octacarbonyl can be used instead of rhodium trichloride.

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Example 14
B sodium cia-propenyl phoaphonate

The Baa procedure of Example 4 is repeated using 20.0 g Binatriura ~ allyl phosphonate instead of diethyl allyl phoa phonate, 50.0 ml water instead of ethanol and 0.2 g iridium » tribromide can be used instead of rhodium trichloride.

Example 15
Calcium-cle ~ propenyl "phosphonate

The procedure of Example 4 is repeated, using 20.0 g Calcium allyl phosphonate instead of diethyl allyl phosphonate, 20.0 ml Iaopropanol instead of ethanol and 0.5 g Huthenium-ehlorid-tetra-triphenylphoepbin trichloride can be used instead of rhodium.

Example 16
Amaonium-cia-propenyl-phosphoaate

The procedure of Example 4 is repeated, using 20.0 g Ammonium allyl phosphonate instead of diethyl allyl phosphonate and 0.3 g of hangan decacarbonyl can be used in place of rhodium trichloride.

Example 17

Ben2ylammonium-ci8-propenyl-pbo3phonat The procedure of Example 4 is repeated, except that 20 "0 g

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Berizylaramonium allyl phosphonate instead of diethyl "allyl phosphonate, 100 ml of acetic acid aneteile of ethanol and 3 g 0 _f · chromium acetoacetonate TRIA instead of Rhoditim trichloride
uses v / earth.

Example 18

Sodium - (*) ■ (ice 1,2 epoxypropyl) phosphona acid

2.2 g (0.018 mol) of cie -propenyl phoephonic acid are dissolved in 10 ml of water. The pH of the aqueous solution is through
Addition of 1.51 g (0.017 mol) of sodium bicarbonate adjusted to 5.5 to 6. 0.55 g (0.0017 mol) of sodium tungstate dihydrate are added, and the almost neutral solution is placed in a water bath and heated to 55 ° C. The water bath is then removed and 2 ml of 30% hydrogen peroxide is added to the reaction mixture over 10 minutes. The reaction is exothermic and the temperature rises
during the addition of the peroxide to 65 ° C. at _c additional
1.6 ml of hydrogen peroxide are added. During the addition, oxygen evolves from the solution, the temperature remains at 55 to 57 ^° C. without external heating
After standing for 20 minutes, the temperature drops to 53 ° C. That
The reaction mixture is then added to a water bath
Heated to 55 ° C for 20 minutes. After that the solution
freeze dried. The monosodium salt is obtained
(i) ~ (cia-1,2 «epoxypropyl) ~ phosphonic acid as a white powder, which is characterized by vapor phase chromatography and nuclear magnetic resonance spectra.

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Example 19 Ammonium - (<t) .- (cia-1, 2 ~ epoxypropyl) - phosphonate

0.4 mol of ammonium cis propenyl ^ phosphonate are dissolved in 10.0 ml of water and treated with 10.0 mg of sodium tungstate. The mixture is heated to 55 ° 0 on a water bath. 5.0 cm ^{5 of} hydrogen peroxide is slowly added and heating to 55 ° C is continued for 1 1/2 hours. The reaction mixture is cooled to room temperature and the solvent is removed by freeze drying. The residue is dissolved in 50 ml of methanol and the solids are separated by filtration. The filtrate is evaporated to dryness.

Example 20

Dl-n-hexyl-ols-o-phenyl-phosphonate ~ "

A mixture of 20.0 g of di n -hexyl allyl phosphonate, 0.2 g Rhodium trichloride and 40 ml of hexane are placed in a pressure vessel. The vessel is filled with hydrogen up to a pressure 0.141 atmospheres (2 psig) filled and sealed. The contents of the vessel is heated to 100 ° C for 2 hours. The vessel is ventilated at ordinary temperature and the contents filtered. The filtrate is concentrated. A mixture of cis and trans -di-n-hexyl-propenyl-phosphonate is obtained. The mixture is distilled through a fractionating column under reduced pressure to remove the cis and trans isomers to separate.

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Example 21 Disodium cia-propenyl-phoaphonate

The procedure of Example 20 is repeated, using 20.0 g of disodium allyl phosphonate instead of di ~ n hexyl « allyl-phoaphonate, 50 ml of water instead of hexane and 0.5 g Manganese decacarbonyl can be used instead of rhodium trichloride

Example 22
Dlpropargyl-cls-propenyl-phosphonate

The procedure of Example 20 is repeated, wherein 20.0 g dipropargyl allyl phosphonate instead of di- * n-hexylallyl phosphonate, 40 ml of benzene was used instead of hexane and 0.5 g of irldium tribromide was used instead of rhodium trichloride will·

The (-) - (cie-i, 2-epoxypropyl) -phosphonaic acid, on which here is referred to, rotates linearly polarized light counterclockwise (viewed from the observer to left) when turning your disodium ealeee in water (Consentration £ 5) is measured at 405 mu.

The term "ice" used in the description of the _f 1 2-epoxypropyl ~ ~ phosphon8tture compounds means that any of the atoms to the carbon 1 and 2 of propyl phoephonsäure bonded hydrogen atoms at the same side dee oxide "ring stands.

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Claims (3)

1g 161 May 12, 1969 Patent to β ρ rü che Process for the production of propenyl phosphoric acid and their esters and salts, characterized in that a compound from the group of allyl phcephonic acid, whose Esters and their salts in the presence of a proton release the solvent with a transition metal catalyst treated. 2. The method according to claim 1, characterized in that the proton-donating solvent is selected from the group consisting of water, alcohols, ketones, carboxylic acids and mineral acids selects. 3. The method according to claim 1, characterized in that the solvent is an inert organic solvent and the reaction is carried out in the presence of hydrogen performs. 18 - BATH ORIGINAL 008808/1805